Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing’s syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation)

Cardiovascular complications of mild autonomous cortisol secretion

Adrenal incidentalomas (AI) may be associated with a mild autonomous cortisol secretion (MACS) in up to one third of cases. There is growing evidence that MACS patients actually present increased risk of cardiovascular disease and higher mortality rate, driven by increased prevalence of known cardiovascular risk factors, as well as accelerated cardiovascular remodelling. Adrenalectomy seems to have cardiometabolic beneficial effects in MACS patients but their management is still a debated topic due to the lack of high-quality studies. Several studies suggested that so called "non-functioning" AI may be actually "functioning" with an associated increased cardiovascular risk. Although the individual cortisol sensitivity and peripheral activation have been recently suggested to play a role in influencing the cardiovascular risk even in apparently eucortisolemic patients, to date the degree of cortisol secretion, as mirrored by the cortisol levels after dexamethasone suppression test remains the best predictor of an increased cardiovascular risk in AI patients. However, whether or not the currently used cut-off set at 50 nmol/L for cortisol levels after dexamethasone suppression could be considered completely reliable in ruling out hypercortisolism remains unclear